Regional Difference in Myelination in Monocarboxylate Transporter 8 Deficiency: Case Reports and Literature Review of Cases in Japan

Background: Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transmembrane transporter protein. MCT8 deficiency induces severe X-linked psychomotor retardation. Previous reports have documented delayed myelination in the central white matter (WM) in these patients; however, the regional pattern of myelination has not been fully elucidated. Here, we describe the regional evaluation of myelination in four patients with MCT8 deficiency. We also reviewed the myelination status of previously reported Japanese patients with MCT8 deficiency based on magnetic resonance imaging (MRI).Case Reports: Four patients were genetically diagnosed with MCT8 deficiency at the age of 4–9 months. In infancy, MRI signal of myelination was observed mainly in the cerebellar WM, posterior limb of internal capsule, and the optic radiation. There was progression of myelination with increase in age.Discussion: We identified 36 patients with MCT8 deficiency from 25 families reported from Japan. The available MRI images were obtained at the age of <2 years in 13 patients, between 2 and 4 years in six patients, between 4 and 6 years in three patients, and at ≥6 years in eight patients. Cerebellar WM, posterior limb of internal capsule, and optic radiation showed MRI signal of myelination by the age of 2 years, followed by centrum semiovale and corpus callosum by the age of 4 years. Most regions except for deep anterior WM showed MRI signal of myelination at the age of 6 years.Conclusion: The sequential pattern of myelination in patients with MCT8 deficiency was largely similar to that in normal children; however, delayed myelination of the deep anterior WM was a remarkable finding. Further studies are required to characterize the imaging features of patients with MCT8 deficiency.

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Consequences of Monocarboxylate Transporter 8 Deficiency for Renal Transport and Metabolism of Thyroid Hormones in Mice

Endocrinology ◽

10.1210/en.2009-1053 ◽

2010 ◽

Vol 151 (2) ◽

pp. 802-809 ◽

Cited By ~ 41

Author(s):

Marija Trajkovic-Arsic ◽

Theo J. Visser ◽

Veerle M. Darras ◽

Edith C. H. Friesema ◽

Bernhard Schlott ◽

...

Keyword(s):

Thyroid Hormone ◽

Thyroid Hormones ◽

Psychomotor Retardation ◽

High Serum ◽

Monocarboxylate Transporter ◽

Iodothyronine Deiodinase ◽

Serum T4 ◽

Mct8 Deficiency ◽

Low Serum

Patients carrying inactivating mutations in the gene encoding the thyroid hormone transporting monocarboxylate transporter (MCT)-8 suffer from a severe form of psychomotor retardation and exhibit abnormal serum thyroid hormone levels. The thyroidal phenotype characterized by high-serum T3 and low-serum T4 levels is also found in mice mutants deficient in MCT8 although the cause of these abnormalities is still unknown. Here we describe the consequences of MCT8 deficiency for renal thyroid hormone transport, metabolism, and function by studying MCT8 null mice and wild-type littermates. Whereas serum and urinary parameters do not indicate a strongly altered renal function, a pronounced induction of iodothyronine deiodinase type 1 expression together with increased renal T3 and T4 content point to a general hyperthyroid state of the kidneys in the absence of MCT8. Surprisingly, accumulation of peripherally injected T4 and T3 into the kidneys was found to be enhanced in the absence of MCT8, indicating that MCT8 deficiency either directly interferes with the renal efflux of thyroid hormones or activates indirectly other renal thyroid hormone transporters that preferentially mediate the renal uptake of thyroid hormones. Our findings indicate that the enhanced uptake and accumulation of T4 in the kidneys of MCT8 null mice together with the increased renal conversion of T4 into T3 by increased renal deiodinase type 1 activities contributes to the generation of the low-serum T4 and the increase in circulating T3 levels, a hallmark of MCT8 deficiency.

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Oligodendroglial Lineage Cells in Thyroid Hormone-Deprived Conditions

Stem Cells International ◽

10.1155/2019/5496891 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 3

Author(s):

Min Joung Kim ◽

Steven Petratos

Keyword(s):

Thyroid Hormone ◽

Psychomotor Retardation ◽

Monocarboxylate Transporter ◽

Therapeutic Effects ◽

Relapsing Remitting ◽

The Central Nervous System ◽

Oligodendrocyte Precursor ◽

Extracellular Transport ◽

Synaptic Dynamics ◽

Mct8 Deficiency

Oligodendrocytes are supporting glial cells that ensure the metabolism and homeostasis of neurons with specific synaptic axoglial interactions in the central nervous system. These require key myelinating glial trophic signals important for growth and metabolism. Thyroid hormone (TH) is one such trophic signal that regulates oligodendrocyte maturation, myelination, and oligodendroglial synaptic dynamics via either genomic or nongenomic pathways. The intracellular and extracellular transport of TH is facilitated by a specific transmembrane transporter known as the monocarboxylate transporter 8 (MCT8). Dysfunction of the MCT8 due to mutation, inhibition, or downregulation during brain development leads to inherited hypomyelination, which manifests as psychomotor retardation in the X-linked inherited Allan-Herndon-Dudley syndrome (AHDS). In particular, oligodendroglial-specific MCT8 deficiency may restrict the intracellular T3 availability, culminating in deficient metabolic communication between the oligodendrocytes and the neurons they ensheath, potentially promulgating neurodegenerative adult diseases such as multiple sclerosis (MS). Based on the therapeutic effects exhibited by TH in various preclinical studies, particularly related to its remyelinating potential, TH has now entered the initial stages of a clinical trial to test the therapeutic efficacy in relapsing-remitting MS patients (NCT02506751). However, TH analogs, such as DITPA or Triac, may well serve as future therapeutic options to rescue mature oligodendrocytes and/or promote oligodendrocyte precursor cell differentiation in an environment of MCT8 deficiency within the CNS. This review outlines the therapeutic strategies to overcome the differentiation blockade of oligodendrocyte precursors and maintain mature axoglial interactions in TH-deprived conditions.

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Isolated peripheral-type facial palsy due to the central lesion:two-case reports

10.21203/rs.2.9279/v1 ◽

2019 ◽

Author(s):

jiwei jiang ◽

Xiuli Shang

Keyword(s):

Facial Palsy ◽

Case Reports ◽

Internal Capsule ◽

High Signal ◽

Posterior Limb ◽

High Risk Factors ◽

Peripheral Facial Palsy ◽

Intensity Lesion ◽

Peripheral Type ◽

The Right

Abstract Background Isolated peripheral facial palsy (P-FP) can lead to lesions involving the inferomedial tegmentum of the pons. However, cases with P-FP in result of a medullary lesion have rarely been reported and result from a paraventricular lesion have never been reported before. Cases presentation We described a 63-year-old man presenting with isolated P-FP due to ipsilateral pontomedullary infarction. Brain diffusion MRI revealed a hyper-intense signal on the left dorsolateral portion of the upper medulla and pontomedullary junction. And then we experienced a 77-year-old man presenting with lateral paraventricular infarction who showed contralateral peripheral type facial palsy. Brain diffusion-weighted image(DWI) showed a high-signal intensity lesion in the right lateral paraventricule and part of the posterior limb of the right internal capsule. Conclusions These two cases caution that a central nervous etiology should be considered in patients with P-FP, especially if they have high risk factors of cerebral infarction.

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Neuroimaging in Neonatal Nonketotic Hyperglycinemia

Journal of Pediatric Epilepsy ◽

10.1055/s-0037-1604293 ◽

2017 ◽

Vol 06 (03) ◽

pp. 161-163

Author(s):

Virupaxi Hattiholi ◽

Mahesh Kamate

Keyword(s):

Intractable Epilepsy ◽

Internal Capsule ◽

Diagnostic Methods ◽

Cerebral Peduncle ◽

Imaging Features ◽

Posterior Limb ◽

Glycine Metabolism ◽

Abnormal Signal Intensity ◽

Central Tegmental Tract ◽

Nonketotic Hyperglycinemia

AbstractNonketotic hyperglycinemia is a fatal disorder of glycine metabolism presenting with intractable epilepsy, hypotonia, and developmental delay in infancy. Diagnostic tests,such as cerebrospinal fluid glycine estimation and genetic diagnostic methods, are not widely available in developing countries and hence many cases are missed or wrongly diagnosed. The magnetic resonance imaging features, such as abnormal signal intensity in the dorsal pons, midbrain, central tegmental tract, cerebral peduncle, and posterior limb of the internal capsule indicate an important clue to the possibility of the disease and help in guiding the treating neonatologist.

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Changes in Thyroid Status During Perinatal Development of MCT8-Deficient Male Mice

Endocrinology ◽

10.1210/en.2012-2031 ◽

2013 ◽

Vol 154 (7) ◽

pp. 2533-2541 ◽

Cited By ~ 47

Author(s):

Alfonso Massimiliano Ferrara ◽

Xiao-Hui Liao ◽

Pilar Gil-Ibáñez ◽

Teresa Marcinkowski ◽

Juan Bernal ◽

...

Keyword(s):

Cerebral Cortex ◽

Gene Mutations ◽

Perinatal Period ◽

Deficiency Syndrome ◽

Psychomotor Retardation ◽

Relative Increase ◽

Monocarboxylate Transporter ◽

Adult Mice ◽

Mct8 Deficiency ◽

Deficient Mice

Abstract Patients with the monocarboxylate transporter 8 (MCT8) deficiency syndrome present with a severe psychomotor retardation and abnormal serum thyroid hormone (TH) levels, consisting of high T3 and low T4 and rT3. Mice deficient in Mct8 replicate the thyroid phenotype of patients with the MCT8 gene mutations. We analyzed the serum TH levels and action in the cerebral cortex and in the liver during the perinatal period of mice deficient in Mct8 to assess how the thyroid abnormalities of Mct8 deficiency develop and to study the thyroidal status of specific tissues. During perinatal life, the thyroid phenotype of Mct8-deficient mice is different from that of adult mice. They manifest hyperthyroxinemia at embryonic day 18 and postnatal day 0. This perinatal hyperthyroxinemia is accompanied by manifestations of TH excess as evidenced by a relative increase in the expression of genes positively regulated by T3 in both the cerebral cortex and liver. An increased tissue accumulation of T4 and T3 and the expression of TH alternative transporters, including Lat1, Lat2, Oatp1c1, and Oatp3a1 in the cortex and Lat2 and Oatp1b2 in the liver, suggested that Mct8 deficiency either directly interferes with tissue efflux of TH or indirectly activates other transporters to increase TH uptake. This report is the first to identify that the ontogenesis of TH abnormalities in Mct8-deficient mice manifests with TH excess in the perinatal period.

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High T3, Low T4 Serum Levels in Mct8 Deficiency Are Not Caused by Increased Hepatic Conversion through Type I Deiodinase

European Thyroid Journal ◽

10.1159/000381021 ◽

2015 ◽

Vol 4 (Suppl. 1) ◽

pp. 87-91 ◽

Cited By ~ 6

Author(s):

Eva K. Wirth ◽

Eddy Rijntjes ◽

Franziska Meyer ◽

Josef Köhrle ◽

Ulrich Schweizer

Keyword(s):

Thyroid Hormone ◽

Serum Levels ◽

Underlying Mechanism ◽

Psychomotor Retardation ◽

Monocarboxylate Transporter ◽

Type I ◽

Hormone Levels ◽

Thyroid Hormone Levels ◽

Mct8 Deficiency ◽

Deficient Mice

Background: The Allan-Herndon-Dudley syndrome is a severe psychomotor retardation accompanied by specific changes in circulating thyroid hormone levels (high T3, low T4). These are caused by mutations in the thyroid hormone transmembrane transport protein monocarboxylate transporter 8 (MCT8). Objective: To test the hypothesis that circulating low T4 and high T3 levels are caused by enhanced conversion of T4 via increased activity of hepatic type I deiodinase (Dio1). Methods: We crossed mice deficient in Mct8 with mice lacking Dio1 activity in hepatocytes. Translation of the selenoenzyme Dio1 was abrogated by hepatocyte-specific inactivation of selenoprotein biosynthesis. Results: Inactivation of Dio1 activity in the livers of global Mct8-deficient mice does not restore normal circulating thyroid hormone levels. Conclusions: Our data suggest that although hepatic Dio1 activity is increased in Mct8-deficient mice, it does not cause the observed abnormal circulating thyroid hormone levels. Since global inactivation of Dio1 in Mct8-deficient mice does normalize circulating thyroid hormone levels, the underlying mechanism and relevant tissues involved remain to be elucidated.

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Deep brain stimulation of the posterior limb of the internal capsule in the treatment of central poststroke neuropathic pain of the lower limb: case series with long-term follow-up and literature review

Journal of Neurosurgery ◽

10.3171/2019.5.jns19227 ◽

2020 ◽

Vol 133 (3) ◽

pp. 830-838 ◽

Cited By ~ 1

Author(s):

Andrea Franzini ◽

Giuseppe Messina ◽

Vincenzo Levi ◽

Antonio D’Ammando ◽

Roberto Cordella ◽

...

Keyword(s):

Neuropathic Pain ◽

Lower Limb ◽

Internal Capsule ◽

Posterior Limb ◽

Vas Score ◽

The Mean ◽

Deep Brain ◽

Stimulation Of

OBJECTIVECentral poststroke neuropathic pain is a debilitating syndrome that is often resistant to medical therapies. Surgical measures include motor cortex stimulation and deep brain stimulation (DBS), which have been used to relieve pain. The aim of this study was to retrospectively assess the safety and long-term efficacy of DBS of the posterior limb of the internal capsule for relieving central poststroke neuropathic pain and associated spasticity affecting the lower limb.METHODSClinical and surgical data were retrospectively collected and analyzed in all patients who had undergone DBS of the posterior limb of the internal capsule to address central poststroke neuropathic pain refractory to conservative measures. In addition, long-term pain intensity and level of satisfaction gained from stimulation were assessed. Pain was evaluated using the visual analog scale (VAS). Information on gait improvement was obtained from medical records, neurological examination, and interview.RESULTSFour patients have undergone the procedure since 2001. No mortality or morbidity related to the surgery was recorded. In three patients, stimulation of the posterior limb of the internal capsule resulted in long-term pain relief; in a fourth patient, the procedure failed to produce any long-lasting positive effect. Two patients obtained a reduction in spasticity and improved motor capability. Before surgery, the mean VAS score was 9 (range 8–10). In the immediate postoperative period and within 1 week after the DBS system had been turned on, the mean VAS score was significantly lower at a mean of 3 (range 0–6). After a mean follow-up of 5.88 years, the mean VAS score was still reduced at 5.5 (range 3–8). The mean percentage of long-term pain reduction was 38.13%.CONCLUSIONSThis series suggests that stimulation of the posterior limb of the internal capsule is safe and effective in treating patients with chronic neuropathic pain affecting the lower limb. The procedure may be a more targeted treatment method than motor cortex stimulation or other neuromodulation techniques in the subset of patients whose pain and spasticity are referred to the lower limbs.

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Minireview: Thyroid Hormone Transporters: The Knowns and the Unknowns

Molecular Endocrinology ◽

10.1210/me.2010-0095 ◽

2011 ◽

Vol 25 (1) ◽

pp. 1-14 ◽

Cited By ~ 256

Author(s):

W. Edward Visser ◽

Edith C. H. Friesema ◽

Theo J. Visser

Keyword(s):

Thyroid Hormone ◽

Organic Anion ◽

Psychomotor Retardation ◽

Cellular Level ◽

Monocarboxylate Transporter ◽

Causative Role ◽

Organic Anion Transporting Polypeptide ◽

Neurological Abnormalities ◽

Knockout Animals

The effects of thyroid hormone (TH) on development and metabolism are exerted at the cellular level. Metabolism and action of TH take place intracellularly, which require transport of the hormone across the plasma membrane. This process is mediated by TH transporter proteins. Many TH transporters have been identified at the molecular level, although a few are classified as specific TH transporters, including monocarboxylate transporter (MCT)8, MCT10, and organic anion-transporting polypeptide 1C1. The importance of TH transporters for physiology has been illustrated dramatically by the causative role of MCT8 mutations in males with psychomotor retardation and abnormal serum TH concentrations. Although Mct8 knockout animals have provided insight in the mechanisms underlying parts of the endocrine phenotype, they lack obvious neurological abnormalities. Thus, the pathogenesis of the neurological abnormalities in males with MCT8 mutations is not fully understood. The prospects of identifying other transporters and transporter-based syndromes promise an exciting future in the TH transporter field.

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A Case of Anterior Choroidal Artery Occlusion and Stroke Secondary to External Compression

Case Reports in Neurology ◽

10.1159/000515574 ◽

2021 ◽

pp. 369-374

Author(s):

Satya Narayana Patro ◽

Khawaja Hassan Haroon ◽

Khansabegum Tamboli ◽

Abdulaziz Zafar ◽

Suhail Hussain ◽

...

Keyword(s):

Medial Temporal Lobe ◽

Optic Tract ◽

Internal Capsule ◽

Cerebral Peduncle ◽

Anterior Choroidal Artery ◽

Vessel Occlusion ◽

External Compression ◽

Posterior Limb ◽

Anterior Choroidal ◽

Choroidal Artery

The anterior choroidal artery (AChA) is a small artery commonly arising from the supraclinoid segment of the internal carotid artery (ICA). The significance of the AChA is related to its strategic supply to various important structures of the brain, such as the optic tract, the posterior limb of the internal capsule, the cerebral peduncle, the lateral geniculate body, medial temporal lobe, medial area of pallidum, and the choroid plexus [J Neurol. 1988;235:387–91]. The AChA syndrome in its complete form consists of the triad of hemiplegia, hemisensory loss, and hemianopia. However, incomplete forms are more frequent in clinical practice [Stroke. 1994;25:837–42]. Isolated infarction in the AChA territory is relatively rare. The presumed pathogenic mechanisms of AChA infarction are cardiac emboli, large-vessel atherosclerosis, dissection of the ICA, small-vessel occlusion, or other determined or undetermined causes [Stroke. 1994;25:837–42 and J Neurol Sci. 2009;281:80–4].

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Arginase Deficiency Presenting as Cerebral Palsy

PEDIATRICS ◽

10.1542/peds.91.5.995 ◽

1993 ◽

Vol 91 (5) ◽

pp. 995-996

Author(s):

ANGELA E. SCHEUERLE ◽

ROBERT MCVIE ◽

ARTHUR L. BEAUDET ◽

STUART K. SHAPIRA

Keyword(s):

Cerebral Palsy ◽

Autosomal Recessive ◽

Urea Cycle ◽

Case Reports ◽

Growth Failure ◽

Autosomal Recessive Disorder ◽

Psychomotor Retardation ◽

Uncomplicated Pregnancy ◽

Arginase Deficiency ◽

Cycle Disorders

Arginase catalyzes the conversion of arginine to ornithine and urea in the final step of the urea cycle. The enzyme deficiency disease, argininemia, is a rare autosomal recessive disorder which presents with progressive psychomotor retardation, growth failure, seizures, and spasticity affecting the lower extremities more than the upper.1 It does not, however, commonly have the severe hyperammonemia seen with other urea cycle disorders.1,2 We describe two unrelated patients, previously thought to have cerebral palsy, who were later found to have arginase deficiency. This suggests that the condition may be underdiagnosed because of its relatively mild symptoms. CASE REPORTS Patient 1, a 9-year-old boy, was born at term after an uncomplicated pregnancy to nonconsanguineous African-American parents.

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